National Advisory Council for Human Genome ResearchSummary of Meeting

Natcher Conference CenterBethesda, Md.

May 10, 2004

The open session of the National Advisory Council for Human Genome Research was convened for its forty-first meeting at 8:40 a.m. on May 10, 2004 at the Natcher Conference Center, Bethesda, Md. Francis Collins, Director of the National Human Genome Research Institute, called the meeting to order.

The meeting was open to the public from 8:40 a.m. until 1:15 p.m. on May 10, 2004. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 1:15 p.m. on May 10, 2004 until adjournment for the review, discussion, and evaluation of grant applications.

Others present for all or a portion of the meeting:

Jennifer Couzin, Science magazineRodney Howell, American College of Medical GeneticsEdward Kloza, NSGCSharon Olson, International Society of Nursing and GeneticsAri Patrinos, Department of Energy

Introduction of Liaisons and New Employees

Mark Guyer welcomed two ad hoc council members: Anne Spence (University of California, Irvine) and James Childress (University of Virginia), and the liaisons to the NACHGR from professional societies: Rodney Howell (American College of Medical Genetics), Ed Kloza (National Society of Genetic Counselors), and Sharon Olson (International Society of Nursing and Genetics). Dr. Guyer then introduced new NHGRI staff members: Cheryl Chick, Grants Management Officer; Michael Shi, Program Director, Genetic Variation; and Jim Inglese, Head of Biomolecular Screening for the NIH Chemical Genomics Center. Finally, Dr. Guyer welcomed members of the press in attendance.

Approval of Minutes

The minutes from the February 9, 2004 Council meeting were approved with one correction: David Burgess should be added to the list of council members in attendance.

Future Meeting Dates

The following dates were proposed for future meetings: September 13-14, 2004, February 7-8, 2005, May 23-24, 2005, September 12-13, 2005, February 13-14, 2006, and May 22-23, 2006.

Director's Report

General Announcements

A Blue Ribbon Panel convened to assess NIH's management of conflict of interest held three meetings during March and April 2004 and presented its report on May 5, 2004. The report included 18 recommendations to achieve balance among several factors -- principles for limiting or eliminating conflict of interest, the need for interaction between the public and private sectors, and the need to recruit the best scientists to NIH. David Burgess, who was a member of the panel, noted that some of the recommendations would require changes in law in order to be implemented.

New NHGRI Initiatives

Two RFAs in the area of sequencing technology development have been issued. One solicited applications for near-term technology development to reduce the cost of genomic DNA sequencing by two orders of magnitude. The second invited proposals to address the longer-term goal of achieving a four-order-of-magnitude cost reduction in about 10 years. The applications were received on April 15, will be reviewed in August, and will be discussed at the September Council meeting.

Another RFA was released to solicit applications to augment the International HapMap Project. The RFA solicited applications for proposals to obtain genotype information for an additional 2.25 million SNPs across the genome in 270 samples from four populations, at high quality and at a fully loaded cost of one cent or less per genotype. The enhanced map of SNPs will enable the Analysis Group to do a better job in picking tag SNPs and therefore increase the power of the HapMap in future association studies.

The Nanomedicine Roadmap Initiative, which is headed by Jeff Schloss from NHGRI and Paul Sieving from NEI, held its Project Launch Meeting on May 4, 2004.

NHGRI and NIGMS hosted a symposium on March 15-16, 2004 entitled, Chemistry and Biology: Partners in Decoding the Genome. The symposium was part of the NIH Roadmap Molecular Libraries Initiative and highlighted scientific insights that have resulted from applying modern chemical approaches to studies of complex biological processes.

Recent Scientific Accomplishments and Issues

NHGRI - Extramural Program

An update of the NHGRI large-scale sequencing program was provided to the Council.

The Rat Genome Sequencing Project Consortium (led by the Baylor College of Medicine Human Genome Sequencing Center) published a paper in the April 1 issue of Nature that described a high-quality draft sequence that covers >90% of the genome of the laboratory rat. In parallel, the international research team and other rat researchers published a set of 30 papers in the April issue of Genome Research further describing the analyses.

On March 1, the first draft of the sequence of the chicken (Gallus gallus) genome was deposited in GenBank by a team from the Washington University Genome Sequencing Center, led by Richard Wilson.

The ENCODE project is now under way. The Consortium conducting the pilot phase of the project meets regularly by teleconference calls, and has established working groups to address several specific issues. A face-to-face meeting of the Consortium will be held June 28-30, 2004 in Rockville, MD. More than 30 applications were received in response to the reissued technology development RFA. These applications will be reviewed in June and discussed at the September Council meeting.

The MGC project, an effort to generate full-length cDNAs for human, mouse, and rat genes, is in the process of awarding new contracts for full-insert cDNA sequencing and to initiate a new set of directed strategies for finding clones corresponding to the genes currently missing from the collection. As of April, 30,000 full-ORF sequences have been submitted to GenBank, mostly from human and mouse. A manuscript describing the status of the project is in press. The annual MGC External Steering Committee Meeting, chaired by Barbara Wold, was held on April 29-30, 2004. Many topics were discussed including how far to push to get cDNA clones for all human and mouse genes, whether to pursue alternative splice variants, and whether the project should consider expanding the goals to include moving the clones into expression-ready vectors. The project is funded by 18 NIH Institutes and co-managed by NCI and NHGRI. NHGRI is in the process of hiring a full-time manager for the MGC project.

On April 14-15, 2004, NCI and NHGRI co-hosted a workshop on "Exploring Cancer through Genomic Sequence Comparisons." This workshop explored state-of-the-art sequencing technologies, discussed different strategies for sequencing tumor genomes, and identified candidate tumors that would be appropriate in the development of a publicly available data set that would include all of the sequence-based variations (e.g., nucleotide changes, interstitial deletions, translocations) associated with tumorigenesis. The workshop recommended the formation of a working group to guide the development of an implementation plan.

NHGRI - Intramural Program

NHGRI, the Office of Rare Diseases, and the Carter Centers for Brain Research in Holoprosencephaly (HPE) and Related Malformations hosted the Third NIH Conference on HPE on the NIH campus April 18-20, 2004.

Office of the Director

On April 30, 2004, as part of the second annual National DNA Day, dozens of researchers and staff from NHGRI visited high schools in rural and urban communities across the country to make presentations and discuss with students the exciting research taking place at NHGRI and the NIH. The U.S. Surgeon General, Richard H. Carmona, joined the participating NHGRI staff in the presentation at the George Washington Carver School in Philadelphia, PA.

As a result of an NIH meeting in November 2003 on the use of genomics to advance treatment for sickle cell disease, a Trans-NIH Sickle Cell Disease Therapies Working Group has been formed. The Working Group includes members from NHGRI, NHLBI, NINDS, NICHD, NIDDK, FIC, NCHMD, and ORD, and is co-chaired by Alan Guttmacher (NHGRI) and Greg Evans (NHLBI). A listserv is being created to facilitate communication with the sickle cell disease research community, and will include information about the following: upcoming research-related workshops and meetings, funding opportunities, new research publications, clinical trials looking for collaborators and/or subjects, and researchers looking for collaborators or pertinent advice and/or expertise.

A working group has been established to discuss the possibility of developing a large-scale U.S. longitudinal cohort for the prospective study of genetic and environmental influences on common diseases. The 13-member working group is comprised of experts in epidemiology, genetics, environmental science, ethics, public health, economics, and public policy. The group will meet at least three times this spring and summer, and in between meetings will pursue important topics using subgroups, and will also meet by conference call. The objectives of the working group are to identify possible approaches for developing a large-scale US cohort study, to explore the potential for including existing cohorts in such a study, to determine key design features, and to determine how to address community and consent issues, as well as other ELSI-related concerns. One possible model for the study was explored at a meeting in December 2003, in collaboration with NICHD, NHLBI, NIEHS, the CDC, and the EPA, where an expansion of the proposed National Children's Study to include parents and grandparents was considered. To obtain additional information relevant to the planning discussion, NIH issued a Request for Information on May 5, 2004, seeking advice on approaches to developing a large-scale U.S. study of genetics and environmental influences on common diseases. The due date for responses to the RFI is May 28, 2004.

NHGRI hosted a roundtable on race, ethnicity, and genetics on March 8-10, 2004. A group of approximately 40 leading scholars in the fields of genetics, clinical medicine, genome science, anthropology, sociology, history and law shared their expertise and provided insight into many of the complex issues surrounding race and genetics. The discussions from this small group meeting will help guide NHGRI in its endeavors to address this important societal question.

NHGRI hosted a workshop March 23, 2004, to explore the issues and potential policy options surrounding direct to consumer marketing of genetic tests.

NHGRI - Policy

The House and Senate Appropriations Subcommittees have passed their versions of the FY2005 budget and have been attempting to achieve a consensus in the Conference Committee, though many expect this to be impossible before October 1. . Both committees have come close to the President's FY05 budget, which includes a $28 billion or 2.6% increase for the NIH and $493 million for the NHGRI (2.8% over FY 04). At the appropriations hearings on April 21, Dr. Zerhouni highlighted six NIH accomplishments, three of which were in the area of genomics.

Last October, the Senate unanimously passed the Genetic Information Nondiscrimination Act of 2003, but the bill remains at the desk of the Speaker of the House awaiting committee assignment. If no action is taken, the bill will have to start over again next year. The U.S. Chamber of Commerce and the health insurance industry have raised concerns about the bill. There was an editorial advocating for the bill in the Washington Post.

The Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) met on March 1-2, 2004. The committee identified several high priority issues on which to focus for the next one or two years, including genetic discrimination, oversight of genetic technologies, patents and access, large population studies, pharmacogenomics, and direct-to-consumer marketing. The next meeting of the SACGHS will be held June 14-15, 2004.

Report from the Department of Energy

Ari Patrinos provided a report on recent activities at the U.S. Department of Energy (DOE). The JGI has published a paper on human chromosome 19, a manuscript on chromosome 5 is under review, and a paper on the sequencing of chromosome 16 is being prepared. The DOE Joint Genome Institute (JGI) expects to have 8X sequence coverage of the Xenopus tropicalis genome by the end of August. A paper on the sequence of the genome of White-rot fungus (Phanerochaete chrysosporium), an important organism for cellulose degradation, has been accepted by Nature Biotechnology. A paper on the sequence of the genome of an ocean diatom, a major participant in biological "pumping" of carbon to ocean depths, has been submitted to Science. Dr. Patrinos reported that sequence coverage of the poplar genome has risen to 8X. The genome of the soybean rust fungus has been sequenced to high draft. In all, ten microbial genomes have been finished at Los Alamos National Laboratory recently. The approximate capacity of the Joint Genome Institute is about 2 billion bases per month. DOE has begun an initiative to make 60% of the JGI's sequencing capacity available to the community. Fifty-six proposals were received for peer review. The committee binned them into five categories and set priorities on which organisms would be sequenced first.

Four linked core research facilities are planned for the Genomes To Life (GTL) program -- a facility for the production and characterization of proteins and molecular tags, one for the characterization and imaging of molecular machines, one for whole proteome analysis, and one for the analysis and modeling of cellular systems and microbial community dynamics. The GTL program will advance the science and help solve DOE mission challenges in energy production, global climate change mitigation, and environmental cleanup. Council commented that it would like to see close coordination of the efforts of the DOE and NHGRI to choose future sequencing projects.

DIR Report

Eric Green reported on the status of the NHGRI Division of Intramural Research (DIR). The fundamental mission of the program is to identify the molecular basis of human disease and to develop effective diagnostic and therapeutic interventions. Today, the program has grown to a staff of over 400 individuals in 25 independent laboratories. There are 42 faculty members, 75 post-doctoral fellows, 10 graduate students, 10 medical genetics fellows, 13 genetic counseling students, and 23 other trainees.

The DIR is comprised of seven units -- the Genetic Disease Research Branch, the Genetics and Molecular Biology Branch, the Cancer Genetics Branch, the Genome Technology Branch, the Social and Behavioral Research Branch, the Medical Genetics Branch, and the Inherited Disease Research Branch. The Board of Scientific Counselors oversees the science and conducts mandatory reviews of each Branch every four years.

The DIR's laboratories are currently located in buildings 10, 49, and 50 on the NIH campus. The program is expanding to a number of buildings in the area including the Twinbrook Research Building in September 2004, the zebrafish facility in building 6C in 2006 (jointly assigned to NHGRI and NICHD and is one of the largest zebrafish facilities in the country). The John E. Porter Neuroscience Research Center will open in late 2004 and DIR will be allocated space based on NHGRI's contribution to neuroscience research. Space in the Mark O. Hatfield Clinical Research Center will be occupied later this year.

The FY04 budget for DIR is $94.5M, which is about 18% of the NHGRI budget.

The DIR has a number of new and expanded programs including the Social and Behavioral Research Branch headed by Colleen McBride, the Cancer Genetics Branch, which is currently searching for a new chief, the Bioinformatics Research Program, and the first NIH Chemical Genomics Center. The Physician-Scientist Development Program plans to take one clinician per year and provide appropriate resources and intense mentoring in the area of translational research.

Council discussed the role that the NIH Intramural Sequencing Center (NISC) has with other NIH institutes who use the center's sequencing capacity on a fee-for-service basis. Council also discussed what companion programs DER has to train clinicians. There is an NIH wide medical student loan repayment program.

Colleen McBride then spoke about the new Social and Behavioral Research Branch (SBRB). The program began eight months ago and has conducted several planning activities, including a retreat, an inaugural forum, and scientific advisory meetings. The mission of the program is on applying genomic discoveries to improve risk communication and comprehension, genetic counseling methods, and prevention interventions. The program also focuses on understanding how social factors influence genomic discoveries and research and investigating emerging ethical and public policy implications of genomic research.

Future directions of the SBRB program include evaluating genetic risk communication to determine how best to convey complex risk messages to maximize comprehension and minimize biased processing, evaluating genetic counseling interventions that optimize decision and behavioral outcomes that can be exported to new situations and may not involve genetics specialists, evaluating channel modalities (e.g., tailored print, lay health advisors, web-based), matching target populations, exploring differences in comprehension of risk communication, and uptake of testing and preventive behaviors.

Road Map Update

Mark Guyer provided an update on the NIH Roadmap process and the role of the NHGRI Advisory Council. The NIH Roadmap is intended to address major opportunities and gaps in biomedical research that no single Institute could take on by itself, and which the agency as a whole must address in order to make the biggest impact possible on the progress of biomedical research. The Roadmap initiatives are intended to catalyze changes that will transform exciting new scientific knowledge into tangible benefits. Regardless of the particular theme or initiative, Roadmap research is intended to be novel, groundbreaking, and not business as usual.

The Road Map has three major themes: new pathways to discovery, research teams of the future, and re-engineering the clinical research enterprise. The NIH Director's fund and contributions from all of the institutes in proportion to their appropriated budgets will provide $128M in funding in FY04 for the initiatives.

Research teams of the future - public-private partnerships; interdisciplinary research teams; and high-risk research through the NIH Director's Pioneer Award (N.B., over 1300 nominations were received in response to the call for nominations for the Pioneer Award. The NIH is currently in process of reviewing these internally).

Each Roadmap initiative is written and issued collaboratively by NIH staff from many ICs who, as a group, constitute the Project Team. In order to deal with the administrative aspects, a single IC is designated as the lead IC for each initiative.

The role of Council, except for the NIH Director's award, will be to provide a second-level of review for each Roadmap initiative for which that institute is the lead IC (the Pioneer Awards will receive second level review by the Advisory Council of the Director, NIH). The Council members will act as advisors to the NIH rather than to the individual IC on whose council they participate. The council review should also take into consideration that some ICs may be interested in funding applications that may be beyond the Roadmap funding plan. Each council will be provided information about all of the initiatives, including applications received, on which institute is the lead, and the recommendations for each of the initiatives.

NHGRI staff is actively involved in the development and organization of four initiatives including the Building Blocks, Pathways, and Networks Implementation Group, the Molecular Libraries and Imaging Implementation Group, the Bioinformatics and Computational Biology Implementation Group, and the Nanomedicine Implementation Group.

Council discussed how public-private partnerships will fit into the Roadmap process. Council was concerned that the Pioneer Awards seemed to be committing a relatively small amount of money to senior researchers in the field. They were also concerned whether institutes would make a commitment to continue funding the research, once the Pioneer Award ends. Council also saw the need for new initiatives to be added to the Roadmap process, but was concerned that these would not be developed if NIH funding decreases or remains the same. Council discussed the need for the working groups to continue to push across NIH procedural boundaries during this process. Council would like to get feedback from the working groups on their work and experience and have them discuss how the Roadmap strategy is evolving.

HapMap Update

Lisa Brooks gave an update on the International HapMap project. There are currently 8.8 million SNPs in dbSNP, of which 3.5 million are "double-hit" (both alleles have been observed at least twice). The CEPH samples are currently being studied and the Yoruba, Japanese, and Han Chinese samples are expected to be available for analysis by June. A paper on the ethical and cultural issues is scheduled to appear in the June issue of Nature Reviews Genetics. Papers on the community engagement process and on the data analyses are being drafted. The International HapMap Consortium will author a paper on the analysis of the 5 kb map later this year. The centers plan to genotype approximately 600,000 SNPs in all four sets of samples, across the genome, excluding the non-genotypable regions. The Consortium is also encouraging groups to submit failed data to the DCC along with their successful data.

The first data quality exercise showed 99.2% concordance and 99.5% accuracy by all groups. In the second QA exercise, all centers will look at 136 SNPs genotyped previously by another center.

The Data Analysis Group held a community meeting in April in Baltimore, MD to give scientists in the field a chance to learn about the project and present their method of haplotype analysis. The Analysis Group is currently working to answer a number of questions for the project including where more SNPs are needed, rules for stopping, how regions of high LD should be defined, and how tag SNPs be chosen.

An RFA for high-throughput genotyping was released on April 16, 2004 by NHGRI. This new RFA was motivated by the early analysis of the ENCODE data and the realization that the planned SNP map would be a valuable research tool, but that it would probably not be dense enough for good coverage in the Yoruba samples. Since there are almost 8 million SNPs in dbSNP and the cost of genotyping has decreased considerably since the beginning of the project, this opportunity will allow the HapMap Consortium to improve the quality of the map and increase its utility for future disease association studies.

The RFA will solicit applications to genotype 2.25 million SNPs across the genome in all four samples at the cost of 1 cent per genotype (vs. 20 cents average cost only 18 months ago). NHGRI has set aside $6.5M for this effort, which will be reviewed by Council at its September meeting. The Consortium will hold their next face-to-face meeting May 11-12, 2004, at Cold Spring Harbor.

New Directions for Sickle Cell Disease Therapy in the Genome Era

NHGRI, NHLBI, NIDDK, the Office of Rare Diseases, FIC, and the Foundation for the NIH convened an international workshop of over 120 attendees on November 19-21, 2003 to discuss "New Directions for Sickle Cell Therapy in the Genome Era." The purpose of this conference was to consider how the new tools and techniques of genomics might be applied both to understand more fully the biology of sickle cell disease and to develop more effective therapeutic strategies for the disease. Sickle cell disease has global health implications and is arguably the first disease whose genetic basis was understood. Pre-genomic approaches for therapies have been tried, and some progress has been made, but the search for a widely available cure has remained elusive.

The major recommendations of the workshop included:

The development of an innovative multidisciplinary sickle cell disease research network.

Bringing new people and disciplines in the field and training the next generation of researchers. This would include integrating genomics and proteomics.

Applying small molecule approaches to look for new therapeutic agents.

The workshop led to the formation of a trans-NIH working group comprised of eight Institutes that developed the following initiatives:

The SCD Research Listserv has been established to accelerate sickle cell disease research by providing a means for rapid, free communication with and among Sickle Cell Disease researchers.

The SCD Clinical Research Network will address critical issues in the care of persons with Sickle Cell Disease through the development of a registry and completion of phase I-III clinical trials.

Novel Idea Grants for new therapies for SCD will support pilot and feasibility studies for novel approaches to develop new therapies for SCD.

ELSI Research will be conducted to identify and explore the ethical issues raised by applying genomics to study Sickle Cell Disease.

Resources for Late Stage Drug Development for Sickle Cell Disease will help improve access by investigators to expertise and resources for moving potential new drugs for sickle cell disease through the required clinical and regulatory processes into the marketplace.

Refinement of Hemoglobin Gene Transfer Vectors for Clinical Applications to Sickle Cell Disease & Cooley's Anemia will support focused refinement of safety features of lentiviral hemoglobin gene transfer vectors as a prelude to ex vivo clinical trials of hemoglobin gene transfer as a therapeutic modality for Sickle Cell Disease and Cooley's anemia.

Searching for Modifier Genes in Sickle Cell Disease will help to identify genes that modify the phenotypic effects of mutations in HBB and to study the mechanisms and effects of such modification.

Concept Clearance: Training Program - Application of Genomics and Proteomics Technologies to Hemoglobinopathies

Bettie Graham presented a concept clearance for a T90 Institutional Training Grant program to train the next generation of hemoglobinopathy researchers, who will utilize genomic and proteomic technologies to facilitate the understanding of the biology of hemoglobinopathies in order to prevent disease and/or to develop effective therapeutic interventions. The program would feature interdisciplinary, institutional postdoctoral programs that would require co-program directors - one who has a research intensive program in hemoglobinopathies and one who has a research intensive program in large-scale genomics and proteomics. The program would include three basic components: didactic training, genomics/proteomics/bioinformatics experience, and research in hemoglobinopathies. Most trainees would be appointed for three years and the total cost per award would be $330,000. Council discussed who would be eligible to apply for this award - both U.S. citizens and people who reside outside of the U.S. are eligible to apply since the T90 Roadmap mechanism allows the support of foreign scientists. They also suggested that a list of people who are interested on both sides be provided to the applicants to help bring them together.

Dr. Guyer presented the concept clearance for an RFA to improve the understanding of the biology of sickle cell disease and to identify promising new agents for sickle cell disease therapy. As part of the Roadmap effort, the NIH is funding a network of Molecular Libraries Screening Centers as a biomedical research resource. This RFA encourages groups to submit proposals on how to best conceptualize the problem and develop high throughput assays to understand the pathophysiology of sickle cell disease. NHGRI would contribute $300,000 in FY05, $800,000 in FY06 and $400,000 in FY07 to fund 6 pilot projects, each for two years. Council discussed the types of assays NHGRI envisioned coming out of this proposal. The concept was accepted.

Council-Initiated Discussion

September Council will have a busy agenda. Currently NHGRI has plans to discuss the budget and sequencing funds, the CEGS program and what we should do about reissuing the program announcement, the RFAs on sequencing technology, the HapMap RFA, and the ENCODE RFA for technology development. Council members may be asked to come for a Sunday evening session.

Announcements and Items of Interest

Dr. Guyer noted the items of interest in the Council folders.

Conflict of Interest

Dr. Guyer read the Conflict of Interest policy to Council and asked them to sign the forms provided.